A prodrug, also referred to as a precursor of a drug, refers to a compound which achieves pharmacological action after the conversion in an organism. A prodrug per se has no or little bioactivity, and releases an active agent after metabolism in vivo. The purpose of investigating and preparing a prodrug is to increase the bioavailability, modify the solubility, enhance the targeting properties, or reduce the toxicity or side effects of the parent drug. It is advantageous for many drugs, especially those having low bioavailability, poor water solubility or high toxic side effects, to be prepared into prodrugs. In general, it is required in clinic that a prodrug can be quickly dissociated into a ligand and a parent drug after entering the body, and the ligand is non-toxic. The parent drug thus released can exert pharmaceutical effects, and the non-toxic ligand is of no harm to the body.
Propofol (i.e., 2,6-diisopropylphenol, also referred to as propofolum) is a short-acting intravenous general anesthetic, having the advantages of rapid onset, no clear accumulation, and rapid and complete recovery. An injection of propofol is used to induce and maintain general anesthesia in clinic.
Despite the excellent anaesthetic effect, propofol is difficult to be formulated as a suitable preparation due to its poor water solubility, and thus it has to be administered as an emulsion via injection in clinic. In view of the above, the propofol preparations currently available have the following disadvantages: 1) they have poor physical stability; 2) they may cause vascular embolization due to large oil drop; 3) they will induce pain in patients due to injection; 4) they can only be mixed with a few injectable products before administration; 5) bacteria tend to grow in an emulsion; and 6) they may cause cardiac toxic and side effects, etc. The application of propofol in clinic is highly limited by these disadvantages.
As such, pharmacists have been trying to eliminate these disadvantages by structural modification, so as to obtain a prodrug having good water solubility while maintaining the anesthetic effect of propofol (see International Journal of Pharmaceutics, 1998, 175:195-204; WO9958555; CN1907954A; and CN102020574).
Among the prodrugs of propofol investigated thus far, the most successful one is Fospropofol reported by Stella et al. (see Water-Soluble Prodrugs of Hindered Alcohols, U.S. Pat. No. 6,451,776). This drug, which is administered via endoscope, is marked by Eisai in 2009. However, hydrolysis of fospropofol in vivo results in not only release of propofol but also production of formaldehyde, which has high toxicity. As such, it was pulled out the market not long after being marketed.